CHAPTER 40 SPINAL DISEASE: NEOPLASTIC, DEGENERATIVE, AND INFECTIVE SPINAL CORD DISEASES AND SPINAL CORD COMPRESSION
The long, cylindrically shaped spinal cord sits within the bony vertebral canal, tightly enveloped by the meninges. It extends from the foramen magnum to the first lumbar vertebra, where it terminates in the conus medullaris. Below this, the lumbosacral nerve roots form the cauda equina. Anatomically, the spinal cord has a distinctive structural arrangement, illustrated in Figure 40-1A. Functionally, the spinal cord plays a key role in sensorimotor conduction. Because of its special features and relatively primitive reflexes, diseases of the spinal cord give rise to a number of distinctive, sometimes overlapping clinical syndromes (Tables 40-1 and 40-2; see Fig. 40-1B).
TABLE 40-1 Red Flag Features Indicative of Cord Disease
TABLE 40-2 Spinal Cord Syndromes
| Syndrome | Features |
|---|---|
| Complete transverse spinal cord syndrome (see Fig. 40-1Bi) | |
| Brown-Séquard (hemicord) syndrome (see Fig. 40-1Bii) | |
| Sensorimotor spinal tract syndrome |
Corticospinal tract involvement: upper motor neuron limb weakness (arm and leg weakness caused by cervical cord lesion; leg weakness caused by a lesion rostral to the upper lumbar spine):
|
| Radicular syndrome | |
| Syringomyelic or central cord syndrome (see Fig. 40-1Biii) | |
| Anterior horn syndrome | Caused by selective involvement of the motor neurons; segmental weakness, atrophy, fasciculations, and absent or diminished reflexes |
| Anterior spinal cord syndrome | Usually associated with vascular lesions of the anterior spinal artery, resulting in ischemia and neurological deficits within its area of supply (see Fig. 40-2); bilateral upper motor neuron weakness and spinothalamic sensory deficit below the lesion; dorsal column function is spared |
| Cauda equina syndrome | Pain usually an early feature; asymmetrical lower motor neuron (areflexic, flaccid, atrophic) paralysis of lower limbs; sphincter dysfunction (urinary or fecal incontinence, diminished anal tone) and radicular sensory loss; may difficult to differentiate clinically from lesions of the lumbosacral plexus |
| Conus medullaris lesions | Early and prominent sphincter dysfunction; back pain; sensory disturbance in sacral dermatomes (perineal: S3-S5; leg: L5-S2); loss of anal tone and reflex; impotence; leg weakness inconsistent, usually mild |
Segmental (myotomal) lower motor neuron weakness, with depressed or absent deep tendon reflexes, muscle atrophy, and flaccidity/decreased tone, may be present at the level of the lesion, as a result of involvement of anterior horn motor neurons or anterior (motor) nerve roots; this helps clinicians localize the lesion (Table 40-3). Segmental (dermatomal) sensory loss may also be present (Fig. 40-2).
TABLE 40-3 Segmental Innervation of Muscles and Tendon and Cutaneous Reflexes
| Segment/Nerve Root | Muscle | Tendon or Cutaneous Reflex |
|---|---|---|
| C3, C4 | Trapezius | — |
| C4, C5 | Rhomboids | — |
| C5 | Deltoid | — |
| C5, C6 | Supraspinatus, infraspinatus, biceps | Biceps reflex |
| C6 | Brachioradialis | Brachioradialis reflex |
| C7 | Triceps, extensor digitorum | Triceps reflex |
| C8 | Flexor digitorum superficialis and profundus | Finger-jerk reflex |
| T1 | Intrinsic muscles of hand | — |
| T7-10 | Upper rectus abdominis | Upper abdominal reflex |
| T10-12 | Lower rectus abdominis | Lower abdominal reflex |
| L1 | Iliopsoas | Cremasteric reflex |
| L2 | Adductor magnus | Adductor and cremasteric reflexes |
| L3, L4 | Quadriceps femoris | Knee-jerk (patellar) reflex |
| L4 | Tibialis anterior | — |
| L5 | Extensor hallucis longus | Plantar reflex |
| L5, S1 | Hamstrings | Ankle-jerk reflex |
| S1 | Extensor digitorum brevis | — |
| S1, S2 | Soleus, gastrocnemius | — |
| S4, S5 | Anal reflex |
Figure 40-2 Distribution of dermatomes on the anterior surface of the body.
(From Merck and Company: Merck Manual of Diagnosis and Therapy, Section 14: Neurologic Disorders; redrawn from Keegan JJ, Garrett FD: The segmental distribution of the cutaneous nerves in the limbs of man. Anat Rec 102:409-437, 1948.)
Radicular symptoms and signs (see Table 40-2) result from irritation and compression of spinal nerve roots by extramedullary spinal cord lesions, usually before the involvement of long tracts (radiculomyelopathy). Radicular features are unusual with intramedullary lesions; when they do occur, they are most often present in the context of demyelinating disease.
Sensorimotor long tract signs usually arise as a result of compression, rather than invasion or destruction, of spinal white matter fasciculi and occur early with intramedullary lesions. Either sensory or motor function may be affected first; the distribution and extent of long tract symptoms and signs are dependent on the site and size of the lesion. A sensory level, below which perception of pain and temperature is altered or lost, is pathognomonic of a spinal cord lesion and should prompt imaging of the spinal cord. Often the signs are subtle in the early stages, and the description of a sensory level should alert the clinician. The highest level of sensory deficit indicates the lower possible level of the lesion, and the pathology may be present anywhere above this level; the sensory level may in fact be well below the actual lesion, and this must be kept in mind when imaging is ordered. Lamination of sensory fibers (see Fig. 40-1A) can give rise to suspended sensory deficits (i.e., isolated sensory deficit) at the level of the lesion or several segments caudally. Sacral sensation may be spared with deeper intramedullary lesions caused by spinothalamic tract lamination. Progressive spinal cord lesions, such as intramedullary neoplasms, may engender sequential deficits.
IMAGING
Magnetic resonance imaging (MRI) has enabled characterization of spinal cord diseases, including their location and internal structure, with the use of different magnetic resonance scanning sequences. The basic spinal MRI study includes T1- and T2-weighted sequences in the sagittal plane and contrast material (gadolinium)–enhanced T1-weighted images in the sagittal and axial planes. Myelography involves the introduction of radiopaque dye to the spinal fluid, through lumbar or sometimes cervical roots, but is limited in resolution and the length of cord that can be imaged in one episode. Obstruction to the cerebrospinal column and distortion and enlargement of the cord may all be directly visualized. Combining myelography with computed tomographic scanning of the spine is useful, allowing a greater extent of the cord to be accurately imaged in the one sitting. Plane films of the spine may reveal bony lesions and other local pathological processes, but their utility is quite limited.
SPINAL CORD INFECTIONS
Potentially any structure of the spinal cord and its surrounding meninges and vertebral column may be involved in infectious processes. The causative agents include bacteria, viruses, parasites, and fungi (Table 40-4).
AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; HTLV-1, human T cell leukemia/lymphoma virus type 1; VZV, varicellazoster virus.
Infectious and Parainfectious Myelopathies
Myelitis is a process intrinsic to the spinal cord; this definition excludes expansive lesions.1 Transverse myelitis is characterized by a focal inflammatory process within the spinal cord, leading to varying degrees of neural injury and dysfunction of neural pathways passing through the inflamed segment.2 This in turn leads to the abrupt onset of varying degrees of weakness, sensory alteration, and autonomic dysfunction.
The diagnostic criteria for transverse myelitis include the following:1,3
Transverse myelitis forms a part of a spectrum of neuroinflammatory conditions and may occur as part of a multifocal central nervous system (CNS) disease, such as multiple sclerosis; as part of a multisystem disease, such as systemic lupus erythematosus; or as an idiopathic, isolated entity.2 Of all cases of idiopathic transverse myelitis, 30% to 60% were preceded by a respiratory, gastrointestinal, or systemic infectious illness.2–5
The underlying pathogenesis of transverse myelitis is varied, depending on the specific underlying disease process. For instance, connective tissue disease–associated transverse myelitis may be secondary to a CNS vasculitis or thrombotic infarction of the cord.6 Most patients have cerebrospinal fluid (CSF) pleocytosis and foci of blood-brain barrier breakdown within the spinal cord.2
Two large etiological groups of inflammatory transverse myelitis are identifiable: the inflammatory demyelinating autoimmune myelopathies, such as multiple sclerosis, and the usually monophasic infectious encephalomyelitides.1 More than 40 such infectious encephalomyelitides have been identified, of which approximately 10 have been established as “pure infectious” myelitides by CSF virus isolation or polymerase chain reaction (PCR) techniques, which indicate that neurological injury resulted directly from microbial infection.1,2,8 The remainder are believed to be parainfectious, caused namely by a microbial infection, which in turn incites an immune response against neural tissue. In the latter, the infection may be remote from the immunological response.2 The latency between myelitis and preceding infection does not significantly differ between infectious and postinfectious myelitis. An interval of 9 ± 6 days has been reported for parainfectious cases, 5 days in mumps-related myelitis, 12 days in zoster-related myelitis, and 10 days in Mycoplasma-related myelitis.3,9–11
Although diagnosis of infectious and parainfectious transverse myelitis requires identification of the infectious agent within the CNS, some autoimmune mechanisms, such as molecular mimicry and superantigen-mediated disease, require only peripheral immune activation.2 In molecular mimicry, the putative mechanism of neural injury is antibody-mediated damage, secondary to cross-reaction of antibodies against an infectious agent with molecularly similar antigens in host neural tissue.2
Transverse myelitis is associated pathologically on tissue sampling (biopsy or autopsy) with inflammation.2 Both gray and white matter compartments are affected, although in postinfectious myelitis, white matter changes, demyelination, and axonal injury are prominent. Focal infiltration by lymphocytes and monocytes into segments of the spinal cord and perivascular spaces and activation of astroglial and microglial cells are observed.2 In some biopsies performed during the acute phase of myelitis, infiltration of CD4+ and CD8+ lymphocytes is prominent. Subsequently, during the subacute phase, monocyte and macrophage infiltration may become more prominent. In cases in which transverse myelitis is associated with autoimmune disease such as systemic lupus erythematosus, focal areas of ischemia or infarction secondary to vasculitis may be present, without prominent inflammation, a finding not usually seen in most cases of infectious transverse myelitis.12
PCR techniques, performed on serum and CSF, have facilitated the rapid, sensitive, and noninvasive diagnosis of many infectious forms, particularly viral, of myelitis.1,13,14 Diagnosis is often based on the detection of viral DNA in CSF by PCR.13 Further supportive evidence for a particular viral agent as the cause of myelitis, of value when viral PCR results are negative, is the presence of specific immunoglobulins M (IgM) and G (IgG) antibodies in the CSF, suggestive of intrathecal synthesis.1,13 This is especially the case when the serum: CSF ratio of these antibodies is depressed in relation to total IgG and albumin levels.
Infectious and parainfectious transverse myelitis are the focus of discussion in this chapter. The list of antecedent infections includes herpesviruses and Listeria monocytogenes, although in most of these cases, causality has not been established. Infectious and parainfectious transverse myelitis can be further subdivided, on the basis of the components of the neural axis involved, into meningomyelitis, transverse myelitis without meningitis, encephalomyelitis, and anterior horn syndrome with meningitis, among other entities.1 Meningitis is defined here as the clinical syndrome of fever and neck stiffness.1,2
Clinical Features
The clinical picture of acute transverse myelitis is one of rapid evolution of neurological deficit; however, the distribution of dysfunction, including the modalities affected, depends on the extent and distribution of inflammation within the spinal cord.2 On examination, there is often a clearly defined level of sensory dysfunction.2 When the maximum level of neurological deficit is reached, approximately 50% of affected patients are paraplegic, and 80% to 94% of patients experience sensory disturbances, including numbness, paresthesias, and bandlike dysesthesias.2–5,15,16 Manifestations of autonomic dysfunction include urinary urgency, urinary or fecal incontinence, difficulty or inability opening bladder or bowels, and sexual dysfunction.1
Imaging
Acute inflammation is evident on spinal MRI.1,2 This includes swelling of the spinal cord, in inflamed segments, as well as increased signal intensity on T2-weighted imaging. In cases in which nerve roots are involved in the inflammatory process (radiculomyelitis), enhancement of the affected nerve roots with administration of intravenous gadolinium contrast material may be seen.2,13 However, there are several reports in the literature of clinical cases of myelitis in which there is no demonstrable abnormality of the spinal cord on imaging.1,2,13
Differentiating between Infectious/Parainfectious Transverse Myelitis and Multiple Sclerosis
In multiple sclerosis, it is unusual to have complete transverse myelitis; there was only one such case of 308 in the Göteborg series.18 The weakness and numbness tend to be less severe in multiple sclerosis.19 Pathologically, CSF oligoclonal bands present in multiple sclerosis are absent in infectious transverse myelitis.1,19 Differences in MRI of the spine are also reported.1,18–20 In multiple sclerosis, the areas of T2 hyperintensity tend to be multifocal, smaller, and limited to one segment of the cord in transverse segments; in infectious and parainfectious transverse myelitis, in contrast, T2 hyperintensities are confluent and elongated, often extending over several spinal segments. Furthermore, plaques of demyelination are usually seen on cerebral MRI in multiple sclerosis but not in infectious transverse myelitis.
Specific Entities
Echovirus meningomyelitis
There have been case reports of echovirus (types 11 and 18) isolated from either pharyngeal exudate or CSF of children with clinical meningomyelitis, with transient T2 hyperintensity of the spinal cord.21,22
Coxsackie virus–related myelitis and meningomyelitis
There exist several case reports of patients with clinical and MRI evidence of transverse myelitis with or without meningitis, from whom Coxsackie virus (B4, B3, B5, A5, and A9) had been isolated or in whom a high titer of specific antibody to this virus had been demonstrated in the CSF or serum.1,23,24 For instance, in one case report of a 6-year-old with rapidly progressive paraplegia, with associated bladder and bowel dysfunction, a rising titer of serum anti-Coxsackie virus B5 antibody was demonstrated.25 The virus was also isolated from the stool. MRI in this case demonstrated diffuse swelling of the spinal cord on T1-weighted imaging.
Mumps-related meningomyelitis
The commonest neurological manifestation of mumps virus infection is meningitis; encephalitis occurs in fewer than 0.1% of cases.9 However, there are case reports of myelitis associated with mumps viremia. For instance, a 10-year-old boy developed flaccid paraparesis and neck stiffness in the setting of parotitis and orchitis that are clinically indicative of mumps infection.26 MRI demonstrated T2 hyperintensity from C2 to T12 spinal cord segments, in keeping with myelitis. Mumps infection was confirmed by the presence of IgM class antibodies against mumps in the serum. In another report, a young woman was diagnosed with mumps-associated transverse myelitis on the basis of clinical findings, MRI demonstration of a swollen spinal cord with uniform high-signal change on T2 weighting, and acute mumps viremia.27 No reports of mumps virus isolation from the CSF, in the setting of transverse myelitis, have been found.
Herpes simplex virus–related myelitis
Although a well-known cause of viral encephalitis, herpes simplex virus (HSV) is a rare cause of myelitis.13,28–30 This entity was first described by Klatersky and associates and has since been reported in both immunocompromised and immunocompetent patients.13,30 Subtle spinal cord involvement by HSV infection may be underrecognized.
HSV type 2 infection and, less frequently, HSV type 1 infection cause genital infection, with vesicles and ulceration.9,32 After primary genital infection, the virus persists latently within the sensory neurons of the dorsal root ganglia and produces recurrent cutaneous disease with intermittent reactivation and retrograde spread along the sensory nerve.9,13,32
On occasion, HSV reactivation may be followed by radiculomyelitis, variably affecting the cauda equina, conus medullaris, and thoracic cord.32 The pathogenesis of HSV-associated myelitis is not well understood, although intra-axonal spread of virus from the sensory ganglion into the spinal cord through the dorsal roots is thought to be the likely mechanism.28 Most cases of HSV-related myelitis described in the literature have been associated with type 2 infection, probably reflective of the recurrence of latent infection mainly with the more commonly HSV type 2 venereal infections.13
In six of a series of nine patients with HSV-related myelitis reported by Nakajima and colleagues, disease onset was marked by bilateral lower limb sensorimotor disturbance and urinary symptoms, with ascending progression of the myelopathy to thoracic or cervical level within the course of a few weeks.13 Most cases of HSV-related myelitis described in the literature followed a similar clinical pattern of an acute, monophasic, usually fatal ascending necrotizing myelitis, with death resulting from respiratory paralysis or meningoencephalitis.13 However, other clinical patterns, including a self-limited, resolving transverse myelitis, a relapsing-remitting form, and chronic myelitis, have been described since the development of improved diagnostic techniques such as PCR which have enabled noninvasive diagnosis.13,28–30,33 In three of the nine patients studied by Nakajima and colleagues, transverse myelitis started in the cervicothoracic cord, with a nonascending pattern and milder sequelae than in the cases of ascending myelitis. There have also been other case reports of transverse myelitis of the cervical and thoracic cord, caused by HSV, that resolved.34 In these cases, demyelination without necrosis was postulated to be the underlying pathological process responsible for myelitis.13
In early reports, HSV-related myelitis was described as being frequently associated, in close temporal relation, with cutaneous herpetic eruptions, which provided a clue as to the diagnosis.13,30 However, it has since then been suggested that this association is seen in very few cases of HSV-related myelitis, and therefore this feature is not useful for early diagnosis. HSV per se is rarely isolated from the CSF.13 Subtle clinical involvement of the spinal cord in patients with genital HSV infections are probably much more common than appreciated, however, and symptoms related to cord involvement are often a prominent feature of the prodromal phase of the illness.
The diagnosis of HSV meningoencephalitis is usually based on the detection of HSV DNA in CSF by PCR, with reported sensitivity and specificity of 98% and 94%, respectively.35 In most cases reported since 2000, PCR has been used in the diagnosis of HSV-related myelitis, although numbers have been too small to obtain data on specificity and sensitivity.28 Further evidence of herpetic infection as the cause of myelitis is the presence of anti-HSV IgM and IgG antibodies in the CSF, suggestive of intrathecal synthesis.28 Although demonstration of seroconversion against HSV concurrent with the episode of myelitis enables diagnosis, it should be kept in mind that anti-HSV antibody titers are not always elevated during the early stage of disease.13 CSF pleocytosis, although usually present, is also not a constant feature.29
MRI findings include enlargement of the conus medullaris; intramedullary T2 hyperintensity, particularly of the posterior funiculi; and gadolinium enhancement of the affected dorsal nerve roots, with no enhancement of the ventral roots.13,28 This is in keeping with the expected pattern of involvement of spinal cord structures, if infection is indeed caused by retrograde spread of virus into the cord from dorsal root ganglia. In one case, both T1 and T2 hyperintensities were observed, suggestive of hemorrhagic necrosis of the affected parts of the cord.13 Follow-up imaging may demonstrate atrophy of the cord in the previously inflamed regions.33
Treatment of HSV-related encephalitis with acyclovir is established; however, there are case reports of the value of this antiviral agent only in the treatment of HSV-related myelitis.28 Corticosteroids, in conjunction with antiviral therapy, may prevent ascending necrotizing myelopathy and improve survival.28 With regard to long-term prognosis, in the series by Nakajima and colleagues, three patients recovered, whereas the remaining six had severe persistent neurological deficits, such as paraplegia, despite antiviral therapy.13
Zoster-related transverse myelitis
Varicellazoster virus (VZV) infection may be associated with a wide spectrum of neurological complications, myelitis being the most poorly characterized of these.36 Several reports describe a postinfectious VZV-related myelitis, which is usually an acute, relatively benign transverse myelopathy, associated with a self-limiting paraparesis and sometimes sensory symptoms and sphincter disturbance.37 Chronic and remitting-relapsing temporal profiles of myelopathy have been described in association with VZV.36
Less commonly, a progressive ascending myelopathy, usually fatal in outcome, is seen in immunocompromised individuals and is thought to be caused by direct VZV invasion of the spinal cord.10,38 Ten cases of necrotizing vasculitis associated with VZV meningoencephalomyelitis have been reported in the literature, all with underlying immunodeficiency, secondary to either malignancy or human immunodeficiency virus (HIV) infection, and all cases fatal within 4 to 32 days.38 The patients typically developed radicular or central back pain within 2 weeks of zoster infection, in association with bilateral motor and sensory signs.
The diagnosis of VZV-related myelitis is historically based on the onset of myelopathy within days to weeks of a typical rash.37 The symptoms may be most pronounced ipsilateral to and at the level of the rash. However, there are reports of VZV-related myelitis, confirmed by positive VZV PCR or culture from the CSF, with no history of cutaneous rash.37,39
VZV per se is rarely isolated from blood or CSF, although the latter usually shows an often profound pleocytosis.37 PCR techniques have enabled the detection of VZV DNA in the CSF of patients suspected of having VZV-related myelopathy, even months later, which enables confirmation of the diagnosis and suggests a role of virus persistence in the pathogenesis of disease.37,38 VZV as the etiological agent in myelopathy is also supported by the presence of antibody (IgG and IgM) to VZV in the CSF, indicative of presence of viral antigen in the nervous system and intrathecal antibody synthesis.37,40
The underlying pathological process in VZV-related myelitis is thought to be a small- or large-vessel vasculopathy, depending on the immune status of the patient.38 Small-vessel disease is seen almost exclusively in immunocompromised patients and includes a necrotizing vasculitis of leptomeningeal vessels, especially around the spinal cord and brainstem.38 VZV has been detected in large and small vessels of the nervous system by PCR, in situ hybridization for VZV antigen, and immunohistochemistry in these cases.38,41,42 Pathological examination may demonstrate intranuclear viral inclusions.38
VZV-related vasculopathy may occur as late as 5 to 6 months after the zoster rash.39 In these patients, the detection of antibody to VZV in CSF, even in the absence of amplifiable VZV DNA, is diagnostic.39,40 There are other reports of zoster-related myelitis in which PCR results for VZV were negative in the presence of anti-VZV antibodies in the CSF or became positive only after several days of clinical symptoms.38,40 It is presumed that the reason why patients with VZV-related vasculopathy may not contain VZV DNA is that active viral replication is confined to CNS arteries.39 Hence CSF PCR for VZV DNA is not as sensitive a test as CSF PCR for HSV.40
MRI demonstrates hyperintensity and swelling, consistent with edema, on T2-weighted sequences.36,38 On T1-weighted images, with gadolinium contrast material, leptomeningeal enhancement over the cerebellum and brainstem is seen in cases of ascending myelitis.38
The treatment of VZV-related myelitis is aggressive antiviral therapy, usually with intravenous acyclovir; however, response is variable.36 VZV strains that are resistant to acyclovir, as well as to related newer compounds such as famciclovir and valacyclovir, have been reported, in both immunodeficient and immunocompetent patients.38,43,44 Resistance results from deficiency or absence of viral thymidine kinase, the enzyme on which these drugs are dependent for intracellular activation via phosphorylation.38,44 These thymidine kinase–deficient VZV mutant strains are, however, susceptible to foscarnet and acyclic nucleoside phosphonates, which are active independently of thymidine kinase.44 Because diagnostic tests for VZV-mediated myelitis are potentially insensitive, management of patients suspected of having this condition should include broadening of antiviral therapy to overcome possible resistance if there is clinical progression or inadequate response to therapy.38
Cytomegalovirus-related myelitis
In the setting of cellular immunodeficiency, such as the acquired immunodeficiency syndrome (AIDS), cytomegalovirus infection of the cord can produce a necrotizing transverse myelitis, typically when CD4 counts are less than 50.45 It is exceedingly rare in immunocompetent persons, although five such cases of cytomegalovirus-associated transverse myelitis were reported by Giobbia and coworkers.46 In all these cases, CSF PCR for cytomegalovirus yielded negative results. The diagnosis was instead obtained on the basis of serological data: namely, cytomegalovirus antigenemia (positivity for cytomegalovirus pp65 antigen) and high serum titers of specific cytomegalovirus IgM and IgG antibodies, positive blood PCR results for cytomegalovirus, and blood or urine cultures. Of note, however, PCR performed on CSF of patients with AIDS demonstrated this test to predict histopathologically confirmed cytomegalovirus-associated CNS disease, including myelitis.47 It is unclear as to whether neuronal injury is immune mediated or caused by a cytotoxic effect of viral infection.
Epstein-Barr virus–related myelitis
Epstein-Barr virus, like VZV, can infect multiples sites of the neuraxis and can therefore produce protean clinical manifestations.48 Both CNS and peripheral nervous system disease can occur, with reports of meningitis, encephalitis, transverse myelitis, neuritis, and overlapping syndromes.48–50 The incidence of Epstein-Barr virus–related neurological disease is not known; however, it has been estimated to occur in 1% to 5% of individuals with infectious mononucleosis.48 The mechanism by which Epstein-Barr virus produces neurological disease is unknown; however, the development of neurological disease over weeks is suggestive of either a subacute to chronic viral infection or a postinfectious, immune-mediated process.48
CSF typically shows pleocytosis, with elevated protein levels.48 The diagnosis is made by the isolation of Epstein-Barr virus DNA from CSF, as well as from peripheral blood monocytes, and the exclusion of other herpesvirus infections through PCR techniques.48,51 Serological evidence is supportive.48 Findings on MRI are variable and may demonstrate increased T2 signal intensity; however, normal findings are also reported in the presence of neurological deficits.48
Unfortunately, no definitive treatment for Epstein-Barr virus nervous system infections exists. Although corticosteroids and immunoglobulins have been used, their effect on disease progression is unknown.48 Antiviral agents have not been shown to be clinically useful. Significant neurological deficits may persist after resolution of the acute phase of myelitis.48,51
Mycoplasma-related myelitis
It is estimated that CNS manifestations, most commonly encephalitis, occur in 1 per 1000 patients with Mycoplasma pneumoniae infections.52 Myelitis, albeit atypical, and radiculitis have been reported in association with meningitis. In 19 cases of Mycoplasma-associated transverse myelitis, patients often developed a flaccid paraparesis, with bladder paresis.11 A definite sensory level was described in only a few cases. There is usually slight CSF pleocytosis, and M. pneumoniae was isolated in at least seven reported cases. In one case, in a patient who had no antecedent respiratory infection, M. pneumoniae was cultivated from a nasopharyngeal aspirate and detected in the CSF by PCR.11,53 Treatment is with doxycycline for 14 days, although the effects of therapy are debated.1 The overall prognosis is generally good, with complete recovery in most cases, although there is one case report of persistent paraplegia after Mycoplasma-associated transverse myelitis.54
Other Rare Infectious Causes of Myelitis
Cases of transverse myelitis associated with Burkholderia pseudomallei (melioidosis) have been described.55 Borrelia recurrentis may also produce myelitis, usually radiculomyelitis rather than isolated myelitis.56 Even so, only 5% of 330 cases of neuroborreliosis were classified as acute meningomyelitis or meningomyeloradiculitis. Transverse myelitis may occur in tuberculous meningitis, usually with severe leptomeningitis.1
Other Myelopathies
Subacute combined degeneration of the cord, classically described in association with vitamin B12 deficiency, affects the posterior and lateral columns of the spinal cord.57 A similar syndrome of posterior column degeneration is also seen in tertiary syphilis (Treponema pallidum infection), and is referred to as tabes dorsalis.57 This manifests clinically with a spastic weakness and ataxia of the lower limbs. Chronic meningeal inflammation may be present and may involve the ventral nerve roots. Other clinical spinal syndromes described in association with syphilitic infection are syphilitic meningomyelitis (a chronic meningitis resulting in subpial myelinated fiber loss, with predominantly bilateral corticospinal tract involvement) and spinal meningovascular syphilis, which may result in an anterior spinal artery syndrome.57
The myelopathy associated with the late stages of AIDS also affects the posterior and lateral columns, as demonstrated in histological studies.1,57 Clinical features of spinal cord disease are often obscured by other neurological complications of AIDS, such as neuropathy and encephalopathy, which result from HIV per se or from opportunistic infections. Vacuolation of myelin and relative sparing of the axons occur, and lipid-laden macrophages are typically abundant.57,58 This vacuolar myopathy was seen in 48% of autopsy examinations of the cord of 90 patients with AIDS, although the frequency of encephalitis was higher in this population.58 There was no correlation between the proviral HIV type I load and the degree of myelopathy.58 Likewise, there was no correlation between opportunistic infections, particularly cytomegalovirus, and the presence and severity of myelopathy. In a separate series of 21 patients with AIDS-associated myelopathy, MRI demonstrated spinal cord atrophy in 15 cases and diffuse intrinsic signal abnormality in six cases.59
Tropical spastic paraparesis is a syndrome of slowly progressive central paraparesis of proximal lower limb dominance, caused by infection with the human T cell leukemia/lymphoma virus type 1 (HTLV-1). Sensory signs are characteristically minimal and usually only in the lower limbs; paresthesias and ataxia, with diminished proprioceptive function and vibration sense, have been described.57,60 Sphincter dysfunction usually occurs early. An associated polyneuropathy has been reported. Levels of CSF antibodies to HTLV-1 are elevated.57 On pathological examination, the corticospinal tracts and posterior columns are affected by an inflammatory myelitis, with focal spongiform demyelination and necrosis.57,60 Foci of gray matter destruction are also seen.
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis occurs typically after childhood viral exanthemata, upper respiratory tract infection, or vaccination, with a short latency.1 Although the majority of postinfectious cases follow viral infections, such as measles, mumps, and Epstein-Barr virus infection, acute disseminated encephalomyelitis can occur after bacterial or parasitic infections.1,2 Most cases are disseminated, as the name implies, with alteration of sensorium; however, in some cases, spinal disease dominates the clinical picture.1
Anterior Horn Cell Syndromes
The hallmark of damage to lower motor neurons is flaccid paralysis. Viral infection and the resultant inflammation cause direct damage to the motor neurons residing in the anterior horns of the spinal cord, producing an anterior myelitis.61 Viral invasion of anterior horn cells usually occurs as part of an acute viral meningitic illness, with fevers, headache, and meningism.61 This is followed by the rapid onset of asymmetrical weakness without any sensory deficits.61 Bulbar and respiratory musculature may be affected, and ventilatory support may be needed. Examination of CSF demonstrates moderate pleocytosis.61 Neurophysiological testing demonstrates low compound muscle action potential, normal sensory nerve action potentials, and sharp waves and fibrillations on electromyography.61
Poliomyelitis
Acute poliomyelitis is now rarely encountered in the industrialized world, because of the World Health Organization’s global eradication program. Nonetheless, pockets of endemic disease persist in sub-Saharan Africa and the Indian subcontinent, and it continues to occur sporadically elsewhere.62 There is also a small incidence of live vaccine–related poliomyelitis.62
Poliomyelitis is caused by an enterovirus whose main route of infection is via the gastrointestinal tract.62 In approximately 5% of infections, after nonspecific flulike symptoms, nervous system infection occurs and is initially manifested as meningitis, with high fevers, neck stiffness, and headache.62 The onset of spinal poliomyelitis is heralded by myalgias, with the subsequent development of asymmetrical, lower limb–predominant flaccid weakness or paralysis, reaching a maximum within 48 hours of onset.62
Diagnosis is based on virus isolation of nasopharyngeal secretions and/or the stool. CSF examination demonstrates elevated protein levels and pleocytosis. Serological diagnosis, with demonstration of antipoliovirus IgG and IgM antibodies, can establish the diagnosis in the absence of viral isolate. PCR techniques now enable rapid diagnosis, identification of serotype, and differentiation of wild-type from vaccine-related disease.63 MRI may demonstrate high signal intensity on T2-weighted imaging in the region of the anterior horn cells.64
There is, unfortunately, no curative treatment.62 Management is supportive, aimed at symptom control with analgesia and prevention of complications. The aim of strict bed rest is to prevent progression of paralysis. Passive exercise during the acute phase, followed by more intensive physiotherapy, can prevent or minimize contractures.65
Poliomyelitis-like Syndromes
Acute flaccid paralysis secondary to anterior horn cell disease may be associated with other enteroviruses (e.g., enterovirus 71, Coxsackie virus A7, echoviruses), tickborne encephalitides, flaviviruses (e.g., Japanese encephalitis, Murray Valley encephalitis virus, and West Nile virus), herpesviruses (cytomegalovirus, Epstein-Barr virus, VZV), and HIV-related opportunistic infections.57,61–68
West Nile virus, a flavivirus, usually causes a mild febrile illness.61 Neurological disease is reported in 1 per 150 infected persons and usually consists of meningitis and encephalitis; however, there are numerous reports of patients with poliomyelitis-like acute flaccid paralysis, occurring during the acute febrile illness.61,68 Diagnosis is based on identification of anti–West Nile virus antibodies in serum or CSF.61 Confirming an anterior horn cell process, high signal intensity in the anterior horns on T2-weighted MRI has been demonstrated.69 Histopathological examination of autopsy specimens has demonstrated anterior myelitis, with perivascular lymphocytic infiltrate, monocytic infiltration, and gliosis.70
Enterovirus 71, which causes outbreaks of hand-foot-and-mouth disease, a common exanthema of childhood characterized by fevers, palmar and plantar rash, and oromucosal ulceration, may be associated with neurological complications, including an acute flaccid paralysis.66
Spinal Epidural Abscess
Spinal epidural abscess is an uncommon condition, occurring with an estimated incidence of 0.2 to 2.8 cases per 10,000 per year.71–74 The incidence peaks in the sixth and seventh decades of life.71 Although this condition is potentially fatal, with devastating neurological sequelae if left untreated, early recognition and prompt institution of appropriate therapy can avert complications.
Risk factors for spinal epidural abscess include immunocompromised states and are identified in Table 40-5.72 In 20% of cases, there is no identifiable risk factor.71,76
TABLE 40-5 Risk Factors for Spinal Epidural Abscess
